Cln1 gene disruption in mice reveals a common pathogenic link between two of the most lethal childhood neurodegenerative lysosomal storage disorders.

Neurodegeneration is a devastating manifestation in the majority of >50 lysosomal storage disorders (LSDs). Neuronal ceroid lipofuscinoses (NCLs) are the most common childhood neurodegenerative LSDs. Mutations in 13 different genes (called CLNs) underlie various types of NCLs, of which the infantile NCL (INCL) and congenital NCL (CNCL) are the most lethal. Although inactivating mutations in the CLN1 gene encoding palmitoyl-protein thioesterase-1 (PPT1) cause INCL, those in the CLN10 gene encoding cathepsin D (CD) underlie CNCL. PPT1 is a lysosomal thioesterase that cleaves the thioester linkage in S-acylated proteins required for their degradation by lysosomal hydrolases like CD. Thus, PPT1 deficiency causes lysosomal accumulation of these lipidated proteins (major constituents of ceroid) leading to INCL. We sought to determine whether there is a common pathogenic link between INCL and CNCL. Using biochemical, histological and confocal microscopic analyses of brain tissues and cells from Cln1(-/-) mice that mimic INCL, we uncovered that Cln10/CD is overexpressed. Although synthesized in the endoplasmic reticulum, the CD-precursor protein (pro-CD) is transported through endosome to the lysosome where it is proteolytically processed to enzymatically active-CD. We found that despite Cln10 overexpression, the maturation of pro-CD to enzymatically active-CD in lysosome was disrupted. This defect impaired lysosomal degradative function causing accumulation of undegraded cargo in lysosome leading to INCL. Notably, treatment of intact Cln1(-/-) mice as well as cultured brain cells derived from these animals with a thioesterase-mimetic small molecule, N-tert-butyl-hydroxylamine, ameliorated the CD-processing defect. Our findings are significant in that they define a pathway in which Cln1 mutations disrupt the maturation of a major degradative enzyme in lysosome contributing to neuropathology in INCL and suggest that lysosomal CD deficiency is a common pathogenic link between INCL and CNCL.

Subpectoral Biceps Tenodesis Using an Expanding PEEK Device.

In this Technical Note, we describe a method of mini-open long head biceps subpectoral tenodesis. The implant used is a threadless expanding PEEK (polyether ether ketone) interference device that fixes the biceps tendon in a drill hole in the humerus under the inferior border of the pectoralis major tendon. The diameter of the drill hole varies between 6 and 8 mm depending on the width of the tendon. The procedure can be performed through a 3-cm incision centered on the inferior border of the pectoralis tendon. Based on our experience, it is a quick, safe, and reliable tenodesis procedure.

Salvage of a Below Knee Amputation Utilizing Rotationplasty Principles in a Patient with Chronic Tibial Osteomyelitis.

INTRODUCTION: Chronic osteomyelitis is a disease that requires fastidious treatment to eliminate. However, when eradication is unable to be achieved through exhaustive modalities of antibiotic therapy and multiple debridements, significant resection of the infected bone and soft tissue must be considered, including amputation. Here we report of a salvage procedure for chronic osteomyelitis of the left tibia by employing a rotationplasty to avoid an above knee amputation and instead provide the patient with a below knee amputation. CASE REPORT: A 51-year-old male presented to the emergency department after noticing dehiscence of an operative wound with exposure of an implant in the left lower extremity. Two years prior to presentation, the patient was involved in a motorcycle accident and underwent four surgeries in the Dominican Republic for an open fracture of the left tibia and fibula, including a procedure that involved the placement of an implant in the left proximal tibia. Tissue biopsies from the wound confirmed that the patient had osteomyelitis of the left proximal tibia. After extensive surgical and antibiotic intervention to eradicate the patient's osteomyeltis, it was eventually determined that an amputation would be necessary. In order to avoid an above knee amputation, a salvage procedure was conducted by employing a rotationplasty to provide the patient with a below knee amputation. CONCLUSION: When amputation is deemed necessary, sparing the knee joint is associated with decreased energy expenditures, increased patient satisfaction and overall better postoperative outcomes. As part of a multi-disciplinary team, orthopaedics, plastic surgery, infectious disease, and medical services successfully treated this case of chronic osteomyelitis of the left proximal tibia by employing a rotationplasty to avoid an above knee amputation and achieve a below knee amputation.

IL-10 suppresses mast cell IgE receptor expression and signaling in vitro and in vivo.

Mast cells are known for their roles in allergy, asthma, systemic anaphylaxis, and inflammatory disease. IL-10 can regulate inflammatory responses and may serve as a natural regulator of mast cell function. We examined the effects of IL-10 on in vitro-cultured mouse and human mast cells, and evaluated the effects of IL-10 on FcepsilonRI in vivo using mouse models. IgE receptor signaling events were also assessed in the presence or absence of IL-10. IL-10 inhibited mouse mast cell FcepsilonRI expression in vitro through a Stat3-dependent process. This down-regulation was consistent in mice tested in vivo, and also on cultured human mast cells. IL-10 diminished expression of the signaling molecules Syk, Fyn, Akt, and Stat5, which could explain its ability to inhibit IgE-mediated activation. Studies of passive systemic anaphylaxis in IL-10-transgenic mice showed that IL-10 overexpression reduced the IgE-mediated anaphylactic response. These data suggest an important regulatory role for IL-10 in dampening mast cell FcepsilonRI expression and function. IL-10 may hence serve as a mediator of mast cell homeostasis, preventing excessive activation and the development of chronic inflammation.